Submissions for variant NM_000059.4(BRCA2):c.6131G>A (p.Gly2044Asp)

dbSNP: rs56191579

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590164	SCV000694941	uncertain significance	not provided	2017-03-13	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6131G>A (p.Gly2044Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 120848 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. UMD/BRCA2 reports this variant in one individual without co-occurrence with deleterious variants; classified as '3-UV'. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV001024926	SCV001187022	likely benign	Hereditary cancer-predisposing syndrome	2019-12-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867904	SCV002241112	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2044 of the BRCA2 protein (p.Gly2044Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 495479). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001024926	SCV003850965	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).